Hypoglycemia is the principal adverse event associated with the pharmacologic management of type 2 diabetes mellitus, and it frequently limits the effectiveness of therapy. Our preliminary studies suggest that sub-intoxicating doses of ethanol are an important mechanism for the development of sulfonylurea-associated hypoglycemia in elderly patients with type 2 diabetes. The purpose of this proposal is to provide rationale for expanded studies into the pathophysiologic effects of ethanol among individuals with type 2 diabetes. I hypothesize that moderate doses of ethanol predispose sulfonylurea-treated patients with type 2 diabetes to hypoglycemic vulnerability by altering one or more of the physiologic processes critical to the defense against hypoglycemia, including (1) direct suppression of counterregulatory hormone release, (2) direct or indirect suppression of hepatic glucose production, and/or (3) reduction of gastrointestinal function with a subsequent delay in carbohydrate absorption. Additionally, I hypothesize that (4) aging will exacerbate the pro-hypoglycemic effects of ethanol, and that (5) the timing of ethanol ingestion relative to meal ingestion will at least partially determine its hypoglycemic potential. To address these hypotheses, I plan to compare the effects of low doses of intravenously and orally administered ethanol on counterregulatory hormone release and recovery from insulin-induced hypoglycemia to placebo among healthy subjects and subjects with type 2 diabetes. Additionally, the effects of administration of intravenous ethanol or its metabolite acetate on parameters of hepatic glucose turnover and lipolysis will be compared to placebo in subjects with type 2 diabetes. I will further examine parameters of gastric motility and function following intravenous and oral administration of ethanol or placebo in subjects with type 2 diabetes and will also compare the metabolic and hormonal responses to moderate doses of ethanol between young and elderly patients with type 2 diabetes mellitus matched for duration of disease. Finally, the effect of ethanol administration with a meal on parameters of overnight glucose homeostasis will be compared to ethanol administration 4 hours after meal ingestion in subjects with type 2 diabetes. These studies will explore clinically important questions that will enhance our understanding of hypoglycemia in type 2 diabetes.